Professional Interests

My lab has a long-term interest in understanding the function of the KDM5 family of transcriptional regulators. KDM5 proteins have a unique combination of chromatin modifying and recognition domains that are likely to regulate gene expression through distinct mechanisms. In addition, an ever-growing body of evidence links their dysregulation to human pathologies. Of the four human KDM5 paralogs (KDM5A-D), three are clinically significant. KDM5A or KDM5B are overexpressed in a large number of cancers, and loss of function mutations in KDM5C are found in patients with X-linked intellectual disability.

To-date, however, no effective therapies exist to treat disorders caused by KDM5 protein dysfunction, primarily because we do not have a comprehensive knowledge of KDM5 target genes, nor of the mechanisms by which KDM5 proteins regulate gene expression. To dissect KDM5 function we use Drosophila since it encodes a single, essential, KDM5 ortholog thereby overcoming the complication of functional redundancy among the four mammalian paralogs.

We currently have a number of projects going on in the lab:

Determining how KDM5 acts with the oncoprotein Myc to regulate cell growth, as this is likely to be directly relevant to understanding how KDM5A/B causes cancer in humans.

Defining KDM5 target genes in larvae and in adults and defining the different mechanisms used by KDM5 to activate and repress gene expression.

Examining neuronal phenotypes of kdm5 mutant flies to gain insight into how loss of human KDM5C results in intellectual disability.

Generating and characterizing mutant fly strains harboring mutations that are analogous to those found in intellectual disability patients. Significantly, all missense mutations in KDM5C found in affected patients occur in evolutionarily conserved residues.